Paroxysmal nocturnal hemoglobinuria (“PNH”) is a blood disorder wherein red blood cells are compromised and are thus destroyed more rapidly than normal red blood cells. PNH results from a mutation of bone marrow cells resulting in the generation of abnormal blood cells. More specifically, PNH is believed to be a disorder of hematopoietic stem cells, which give rise to distinct populations of mature blood cells. The basis of the disease is believed to be somatic mutations leading to the inability to synthesize the glycosyl-phosphatidylinositol (“GPI”) anchor that is responsible for binding proteins to cell membranes. The mutated gene, PIG-A (phosphatidylinositol glycan class A), resides in the X chromosome and can have several different mutations, varying from deletions to point mutations.
PNH causes a sensitivity to complement proteins, which occurs in the cell membrane. PNH cells are deficient in a number of proteins. For example, PNH cells are associated with deficiencies in essential complement-regulating surface proteins. These complement-regulating surface proteins include the decay-accelerating factor (“DAF”) also known as CD55 and membrane inhibitor of reactive lysis (“MIRL”) also known as CD59.
CD59 deficiencies have also been described in the literature to have potential roles in the pathophysiology of the disease including ischemia-reperfusion injury (Yamada et. al. J Immun. 2004; Omidvar et. al. J Immun. 2006, Turnberg et al Amer. J of Pathology 2004) and autoimmune disease, such as lupus erythematosis and rheumatoid arthritis (Kinderlerer et al. Arhritis Research & Therapy 2006, Alahlafi et. al. J Cutaneous Pathology 2005).
There is a continuing need for efficient methods and compositions that can be used to treat, prevent or manage diseases associated with CD59 deficiency, including hemolytic diseases such as, for example, PNH.